Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune , Dr. Homi Bhabha Road, Pune-411008, Maharashtra, India.
Biomacromolecules. 2017 Jan 9;18(1):113-126. doi: 10.1021/acs.biomac.6b01411. Epub 2016 Dec 8.
New cisplatin-stitched polysaccharide vesicular nanocarrier is developed for combination therapy of three clinical important antagonistic drugs together to accomplish synergistic cancer therapy in breast cancer treatment. Carboxylic functionalized dextran was tailor-made for the chemical conjugation of cisplatin, and a renewable hydrophobic unit was anchored in the backbone to interdigitize the chains to self-assemble as cisplatin-stitched polysaccharide nanovesicles. Water-soluble DNA-intercalating drug doxorubicin·HCl (DOX) and water insoluble topoisomerase type I inhibitor drug camptothecin (CPT) were encapsulated in these vesicles to produce dual or triple drug-loaded vesicular nanocarrier. This unique cisplatin, DOX and CPT triple drug-loaded dextran vesicles were stable in aqueous medium, and the vesicular geometry acted as a shield for Pt-polymer drug conjugate against glutathione (GSH) detoxification under physiological conditions. Lysosomal enzymes ruptured the nanovesicle exclusively at the intracellular compartments to deliver the combination of all three drugs simultaneously to maximize the therapeutic efficacies. In vitro cytotoxicity studies revealed that free cisplatin was highly detoxified by the GSH in breast cancer cells, whereas the enhanced stability of Pt-stitched dextran vesicle against GSH facilitated ∼99% cell killing in breast cancer cells. Combination therapy studies revealed that the free cisplatin, DOX, and CPT were found to be antagonistic to each other. Dual drug-loaded vesicles exhibited synergistic cancer cell killing while delivering these antagonistic drugs from a dextran vesicular platform. Remarkable synergistic cell killing was accomplished in cisplatin, DOX, and CPT triple drug-loaded vesicles at nanogram concentrations in breast cancer cells. The internalization of drugs and cellular uptake were confirmed by confocal microscope and flow cytometry analysis. The drugs were taken by the cancer cells in large amounts while delivering them from dextran vesicles compared to their free form. These spectacular results opened new opportunities for synergistic cancer therapy for GSH-overexpressed breast cancer using triple drug-loaded polysaccharide vesicular nanocarriers.
开发了一种新的顺铂缝合多糖囊泡纳米载体，用于三种临床重要拮抗药物的联合治疗，以协同治疗乳腺癌。羧酸功能化葡聚糖被定制用于顺铂的化学偶联，并且可再生的疏水性单元被锚定在主链中，以互穿链自组装为顺铂缝合多糖纳米囊泡。水溶性 DNA 插入药物阿霉素盐酸盐（DOX）和水不溶性拓扑异构酶 I 抑制剂药物喜树碱（CPT）被包裹在这些囊泡中，以产生双载或三载囊泡纳米载体。这种独特的顺铂、DOX 和 CPT 三载葡聚糖囊泡在水介质中稳定，囊泡几何形状作为 Pt-聚合物药物缀合物在生理条件下对抗谷胱甘肽（GSH）解毒的盾牌。溶酶体酶仅在细胞内隔室中破坏纳米囊泡，以同时递送至三种药物的组合，从而最大限度地提高治疗效果。体外细胞毒性研究表明，游离顺铂在乳腺癌细胞中被 GSH 高度解毒，而 GSH 对 Pt 缝合葡聚糖囊泡的增强稳定性促进了约 99%的乳腺癌细胞杀伤。联合治疗研究表明，游离顺铂、DOX 和 CPT 彼此拮抗。双载囊泡表现出协同的癌细胞杀伤作用，同时从葡聚糖囊泡平台递送至这些拮抗药物。在乳腺癌细胞中，以纳克浓度实现了顺铂、DOX 和 CPT 三载囊泡的显著协同细胞杀伤。通过共聚焦显微镜和流式细胞术分析证实了药物的内化和细胞摄取。与游离形式相比，从葡聚糖囊泡递送至癌细胞时，药物的摄取量很大。这些惊人的结果为使用三载多糖囊泡纳米载体对 GSH 过表达的乳腺癌进行协同癌症治疗开辟了新的机会。
